Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pathology

Supervisor

Dr. Ann Chambers

2nd Supervisor

Dr. Alan Tuck

Joint Supervisor

Abstract

Early breast cancer progression involves advancement through specific morphologic stages including atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive mammary carcinoma (IMC), although not always in a linear fashion. Histological studies have examined differences in breast tissues representing these stages of progression, but model systems which allow for experimental testing of factors influencing transition through these stages are scarce. The purpose of these studies was to develop a 3D in vitro model of early breast cancer progression that reflected the in vivo sequence of events, and to use this system to identify and functionally test genes important in controlling the processes. The 21T series cell lines, originally derived from the same patient with metastatic breast cancer, were shown to mimic specific stages of human breast cancer progression (21PT, ADH; 21NT, DCIS; 21MT-1, IMC) when grown in the mammary fat pad of nude mice. When grown in 3D Matrigel, the cell lines showed characteristic morphologies in which aspects of the stage-specific in vivo behaviours were recapitulated.

Gene expression profiling of the 21T cells revealed characteristic patterns for each, with differential expression of certain key genes in common with clinical specimens. Subsequent studies focused on functionally characterizing the roles of VANGL1, S100A2 and TBX3 in breast cancer progression. Genes were up- or down-regulated to determine if alterations could affect transitioning between stages of progression. VANGL1 was differentially expressed in the ADH (21PT) to DCIS (21NT) transition (higher in DCIS) and was found functionally to promote the transition from ADH to a malignant phenotype (DCIS and even IMC). S100A2 and TBX3 were both differentially expressed in the DCIS to IMC (21MT-1) transition (S100A2 lower in IMC, TBX3 higher in IMC). S100A2 was found to functionally inhibit the transition from DCIS to IMC, while TBX3 promoted progression to invasion.

These studies demonstrate that the 21T series cell lines provide a model of early breast cancer progression when grown in 3D. In addition, the model provides a means of testing the functional effects of genes on transitions between stages of pre-malignant to malignant growth, which may elucidate potential therapeutic targets.


Included in

Neoplasms Commons

Share

COinS